The human T lymphotropic virus type I (HTLV-I) is associated with a chronic progressive myelopathy known as HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic progressive form of multiple sclerosis (MS). Other viruses such as human herpes virus type 6 (HHV-6) have also been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aid in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology. Areas of research addressing these neurovirological and neuroimmunological issues include: I) The host immune response to viruses from patients with HAM/TSP and MS with particular focus on virus-specific CD8+ cells; II) The role of HHV-6 in the pathogenesis of MS; III) Immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are; 1) PBMC from patients with HAM/TSP have high levels of HTLV-I proviral DNA and HTLV-I tax mRNA expression. These levels are even higher in patient cerebrospinal fluid (CSF). 2) CD8+ cells have been shown to be an additional peripheral blood reservoir for HTLV-I in addition to CD4+ cells. 3) This high virus load appears to drive HTLV-I specific CD8+ T cell responses as measured by HLA A201 tetramer reactivity. 4) HTLV-I tax 11-19 cells have been shown to be specifically elevated (relative to CMV) in CSF of HAM/TSP patients. 5) We continue to recruit additional HAMTSP patients for a clinical trial of recombinant interferon b1a in HAM/TSP. We have demonstrated a reduction in HTLV-I tax11-19 specific CD8+ T cells and HTLV-I induced spontaneous lymphoproliferation during and after treatment . 6) HHV-6 continues to be detected in cell-free material from MS patients and has been characterized as the HHV-6A variant. 7) HHV-6A specific T cell responses have been shown to be elevated in MS and HHV-6 specific T cell lines have been generated which cross-react with peptides derived from myelin basic protein. 8) Proinflammatory genes, in particular IL-18, have been shown to be increased in HHV-6 infected T cells as demonstrated by microarray analysis. 9) The soluble form of the HHV-6 receptor (CD46) has been shown to be elevated in serum and CSF from MS patients. Collectively, these results continue to define the role of human viruses that are associated with chronic progressive neurologic disease.